1. Field of the Invention
The present invention relates generally to the fields of biology and medicine. In particular, the invention relates to the modulation of the sulfilimine bond between peptides and treatment of conditions by the modulation of the same.
2. Description of Related Art
Collagen IV networks are ancient proteins of basement membranes, a specialized form of extracellular matrix, that underlie epithelia in metazoa from sponge to human. Collagen IV molecules are assembled into networks that serve as a scaffold for the assemblage of BM components (Hudson et al., 2003). The networks confer structural integrity to tissues, serve as scaffolds for the assembly of other macromolecular components, and serve as ligands for integrin cell-surface receptors that mediate cell adhesion, migration, growth and differentiation (Moser et al., 2009; Hynes, 2002; Yurchenco and Furthmayr, 1984). The networks participate in signaling events in Drosophila development, in the clustering of receptors in the development of mammalian neuromuscular junction (Fox et al., 2007), and they are involved in autoimmune and genetic diseases (Gould et al., 2006; Gould et al., 2005; Hudson et al., 2003). The networks are assembled by oligomerization of triple-helical protomers by end-to-end associations and by intertwining of triple helices through their N- and C-terminal domains (Khoshnoodi et al., 2008; Khoshnoodi et al., 2006). At the C-terminus, two protomers associate through their trimeric non-collagenous (NC1) domains forming a hexamer structure. The protomer-protomer interface is covalently crosslinked, a key reinforcement that strengthens the structural integrity of networks. In the case of humans, the crosslink also confers immune privilege to the collagen IV antigen of Goodpasture autoimmune disease (Vanacore et al., 2008; Borza et al., 2005).
The quest for the chemical nature of these crosslinks has been the subject of numerous investigations over the last two decades; yet, the identity of the covalent bond remained unknown. Initially, the crosslinks were identified as disulfide bonds (Siebold et al., 1988), which were subsequently ruled out by the x-ray crystal structure of NC1 hexamers (Sundaramoorthy et al., 2002; Than et al., 2002). Electron density maps suggested connectivity between Methionine-93 (Met93) and Lysine-211 (Lys211) at the interface of adjoining protomers (Than et al., 2002); however, the connectivity is gradually degraded by x-rays, rendering precise characterization a challenge for structural analysis by crystallography (Than et al., 2005; Vanacore et al., 2004).